A drug first identified 150 years ago and used as a smooth-muscle relaxant could make tumours more sensitive to radiation therapy, according to a study.
A drug first identified 150 years ago and used as a smooth-muscle relaxant could make tumours more sensitive to radiation therapy, according to a study. Researchers from Ohio State University (OSU) in the US found that the drug called papaverine, inhibits the respiration of mitochondria, the oxygen-consuming and energy-making components of cells, and sensitises model tumours to radiation. The study, published in the journal Proceedings of the National Academy of Sciences, found that the drug does not affect the radiation sensitivity of well-oxygenated normal tissues.
The researchers showed that modifying the papaverine molecule might improve the safety of the molecule and could represent a new class of radiosensitising drugs that have fewer side effects. “We know that hypoxia (deficiency in the amount of oxygen reaching the tissues) limits the effectiveness of radiation therapy, and that’s a serious clinical problem because more than half of all people with cancer receive radiation therapy at some point in their care,” said Nicholas Denko, a professor at OSU.
“We found that one dose of papaverine prior to radiation therapy reduces mitochondrial respiration, alleviates hypoxia, and greatly enhances the responses of model tumours to radiation,” Denko said. Radiation kills cancer cells in two ways: directly, by damaging DNA, and indirectly, by generating reactive, damage-causing molecules called oxygen radicals.
Hypoxic conditions reduce the generation of radiation-induced DNA damage and the effective toxicity of a dose of radiation. “If malignant cells in hypoxic areas of a tumour survive radiation therapy, they can become a source of tumour recurrence. It is critical that we find ways to overcome this form of treatment resistance,” Denko said.
Tumour hypoxia is a consequence of oxygen demand and supply. Cancer cells require high levels of oxygen to fuel their rapid growth, which can be so great that it outpaces the delivery of oxygen from the blood supply. Poorly formed blood vessels in the tumour are not efficient at delivering oxygen and other nutrients.
Insufficient oxygen causes pockets of dead, necrotic cells surrounded by areas of hypoxia. Cancer cells in hypoxic regions at a distance from the blood vessel can also be beyond the reach of chemotherapy and be resistant to radiation. Strategies to overcome radiation resistance typically focus on delivering more oxygen to the tumour, Denko said.
“But these attempts have met with little clinical success because tumours have poorly formed vasculature,” he said. “We took the opposite approach. Rather than attempting to increase oxygen supply, we reduced the oxygen demand, and these findings suggest that papaverine or a derivative is a promising metabolic radiosensitiser,” Denko said.